Sickle cell

A typical electrospray analysis can be completed in 15 min with as little as 1 pmol of protein. An analysis of the cord blood of a baby (Figure 40.6) showed quite clearly that five globins were present, viz., the normal ones (a, (3, Gy, and Ay) and a sickle-cell variant (sickle (3). The last one is easily revealed in the mass spectrum, even at a level of only 4% in the blood analyzed. 

Electrospray mass spectra of globins from the blood of (a) a child diagnosed as having the sickle-cell anemia trait and (b) of its mother. As well as the usual p-globin sickle-cell variant at m/z 15,837.2, a new variant (P-Montreal-Chori) appears at m/z 15,879.3 and is observed in both the child and the mother. 

Lesk and Chothia did find, however, that there is a striking preferential conservation of the hydrophobic character of the amino acids at the 59 buried positions, but that no such conservation occurs at positions exposed on the surface of the molecule. With a few exceptions on the surface, hydrophobic residues have replaced hydrophilic ones and vice versa. However, the case of sickle-cell hemoglobin, which is described below, shows that a charge balance must be preserved to avoid hydrophobic patches on the surface. In summary, the evolutionary divergence of these nine globins has been constrained primarily by an almost absolute conservation of the hydro-phobicity of the residues buried in the helix-to-helix and helix-to-heme contacts. 

Sickle-cell hemoglobin confers resistance to malaria... 

Sickle-cell anemia is the classic example of an inherited disease that is caused by a change in a protein s amino acid sequence. Linus Pauling proposed in 1949 that it was caused by a defect in the hemoglobin molecule he thus coined the term molecular disease. Seven years later Vernon Ingram showed that the disease was caused by a single mutation, a change in residue 6 of the P chain of hemoglobin from Glu to Val. 

Figure 3.14 Sickle-cell hemoglobin molecules polymerize due to the hydrophobic patch introduced by the mutation Glu 6 to Val in the P chain. The diagram (a) illustrates how this hydrophobic patch (green interacts with a hydrophobic pocket (red) in a second hemoglobin molecule, whose hydrophobic patch interacts with the pocket in a third molecule, and so on. Electron micrographs of sickle-cell hemoglobin fibers are shown in cross-section in (b) and along the fibers in (c). [(b) and (c) from J.T. Finch et al., Proc. Natl. Acad. Set. USA 70 718-722, 1973.)...

Embury, S.H. The clinical pathophysiology of sickle-cell disease. Annu. Rev. Med. 37 361-376, 1986. 

Finch, J.T., et al. Stmcture of sickled erythrocytes and of sickle-cell hemoglobin fibers. Proc. Natl. Acad. Sci. USA 70 718-722, 1973. 

Ingram, V.M. Gene mutation in human haemoglobin the chemical difference between normal and sickle cell haemoglobin. Nature 180 326-328, 1957. 

In certain reglon.s of Africa, tire. sickle-cell trait Is found In 20% of the people. Wiry does snch a deleterious heritable condition persist in dre popnladon For reasons as yet unknown, individnals widr this trait are less sn.scepdble to dre most virnlent form of malaria. The geographic distribn-don of malaria and dre sickle-cell trait are posidvely correlated. 

In the body, proteins are built up by a series of reactions that in general produce a specific sequence of amino adds. Even tiny errors in this sequence may have serious effects. Among the genetic diseases known to be caused by improper sequencing are hemophilia, sickle cell anemia, and albinism. Sickle cell anemia is caused by the substitution of one valine unit for a glutamic add unit in a chain containing 146 monomers. 

In nephrogenic diabetes insipidus the kidney s ability to respond to AVP is impaired by different causes, such as drugs (e.g. lithium), chronic disorders (e.g. sickle cell disease, kidney failure) or inherited genetic disorders (X-linked or autosomal NDI). This type of diabetes insipidus can not be treated by exogenous administration of AVP or AVP analogues. Instead, diuretics (hydrochlorothiazide combined or not with amiloride) and NSAI (indomethacin) are administrated to ameliorate polyuria. 

Intermediate-conductance (IKCa) Sickle cell anemia, Diarrhea, Clotrimazole, ICA-15451 ICA-17043... 

Influenza vaccine. Influenza vaccine is recommended annually for children age > 6 months with certain risk factors (including but not limited to asthma, cardiac disease, sickle cell disease, HIV, diabetes see MMWR. 2001 50(RR-4) 1-44), and can be administered to all others wishing to obtain immunity. Children aged <12 years should receive vaccine in a dosage appropriate for their age (0.25 mL if age 6-35 months or 0.5 mL if age >3 years). Children aged <8 years who are receiving influenza vaccine for the first time should receive two doses separated by at least 4 weeks. 

Kumpati, J. (1987). Liposome-loaded phenylalanine or tryptophan as sickling inhibitor A possible therapy for sickle cell disease, Biochem. Med. Metabol. Biol., 38, 170-181. 

Sebastian P, Ramoni ME, Nolan V, Baldwin CT, Steinberg MH. Genetic dissection and prognostic modeling of overt stroke in sickle cell anemia. Nat Genet 2005 37 435-40. 

Figure 1-1. Examples ofthe two-way street connecting biochemistry and medicine. Knowledge ofthe biochemical molecules shown in the top part of the diagram has clarified our understanding ofthe diseases shown in the bottom half—and conversely, analyses ofthe diseases shown below have cast light on many areas of biochemistry. Note that sickle cell anemia is a genetic disease and that both atherosclerosis and diabetes mellitus have genetic components.

In sickle cell hemoglobin (HbS), Val replaces the P6 Glu of HbA, creating a sticky patch that has a complement on deoxyHb (but not on oxyHb). De-oxyHbS polymerizes at low O2 concentrations, forming fibers that distort erythrocytes into sickle shapes. 

---